Herpes simplex virus type 1 (HSV-1) induces a destructive inflammatory process referred to as herpes stromal keratitis (HSK). Using a mouse model, we have shown that HSK is regulated by CD4+ T cells through the production of the Th1 cytokines interferon gamma (IFN-) and interleukin 2 (IL-2). The available evidence suggests that the chronic inflammation associated with HSK requires an interaction between CD4+ T cells and antigen presenting cells (APCs) in the infected cornea that maintains the activity of both cells. This reciprocal activation results from signaling through pairs of co-stimulatory molecules that are expressed on CD4+ T cells and APCs, and by the cytokine IL-12 and perhaps a newly discovered homologue IL-23 that are produced by APCs and enhance IFN- production by CD4 T cells. Our studies focus on the co-stimulatory pairs B7-CD28, CD40-CD154, and OX40-OX40L. We propose that signaling through CD40 and OX40L is important to maintain IL-12/IL-23 production by APCs in the infected cornea, and becomes increasingly important in the latter stages of HSK, as the antagonistic effects of IL-10 become more pronounced. We further propose that signaling through CD28, OX40, and IL-12/IL-23 receptors is important to provide CD4+ T cells with the signaling threshold required to maintain Th1 cytokine production, and that this co-stimulation becomes increasingly important as HSK progresses and HSV epitope density in the cornea diminishes. We propose that interference with co-stimulatory interactions at inflammatory sites holds significant therapeutic potential, and will exploit the information gained in these studies to develop cocktails of blocking reagents with optimal efficacy for treating HSK.